Enzymatic oxidation of ansa-ferrocifen leads to strong and selective thioredoxin reductase inhibition in vitro - Sorbonne Université Accéder directement au contenu
Article Dans Une Revue Journal of Inorganic Biochemistry Année : 2016

Enzymatic oxidation of ansa-ferrocifen leads to strong and selective thioredoxin reductase inhibition in vitro

Michèle Salmain
Ilaria Ciofini

Résumé

This paper reports the inhibitory effect on the cytosolic thioredoxin reductase (TrxR1) in vitro by the ansa-ferrocifen derivative (ansa-FcdiOH, 1). We found that 1 decreased only slightly enzyme activity (IC50 = 8 μM), while 1*, the species generated by enzymatic oxidation by the HRP (horseradish peroxidase)/H2O2 mixture, strongly inhibited TrxR1 (IC50 = 0.15 μM). At the same concentrations, neither 1 nor 1* had effect on glutathione reductase (GR). The most potent TrxR1 inhibitor did not appear to be the corresponding quinone methide as it was the case for ferrocifens of the acyclic series, or the stabilized carbocation as in the osmocifen series, but rather the quinone methide radical. This hypothesis was confirmed by ab-initio calculations of the species generated by oxidation of 1 and by EPR spectroscopy. BIAM (biotin-conjugated iodoacetamide) assay showed that 1* targeted both cysteine and selenocysteine of the C-terminal redox center of TrxR1.
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Dates et versions

hal-01401089 , version 1 (02-05-2018)

Identifiants

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Valeria Scalcon, Anna Citta, Alessandra Folda, Alberto Bindoli, Michèle Salmain, et al.. Enzymatic oxidation of ansa-ferrocifen leads to strong and selective thioredoxin reductase inhibition in vitro. Journal of Inorganic Biochemistry, 2016, 165, pp.146-151. ⟨10.1016/j.jinorgbio.2016.08.005⟩. ⟨hal-01401089⟩
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